Schematic model of the hypothetical pro-TNFα–TACE complex. The full-length activated TACE consists of the catalytic domain (shown in standard orientation, Fig. 1), a disintegrin-like domain, a Cys-rich moiety, the transmembrane segment, and the intracellular domain. The trimeric pro-TNFα consists of intracellular segments, transmembrane segments, 26–28 residue spacers forming a stalk, and the compact trimeric TNFα cone (28). TACE and pro-TNFα might be anchored in the membrane in such a manner that the TNFα cone is attached to the “right” side of the catalytic domain, with the scissile Ala-76 → Val-77 bond of one extended pro-TNFα strand placed above the active site.